Bone fractures are a major concern for the health care of elderly and women populations. One leading reason for bone fractures is deterioration of tissue quality (manifested by its toughness) in addition to changes in bone mineral density and architecture. Recent evidence has evinced that bone may experience two distinct stages in the post-yield deformation: it begins with acute increases in microdamage accumulation and viscous response (Stage I), followed by plastic deformation and saturation of the viscous response (Stage II). More intriguingly, the internal strains in individual mineral and collagen phases appear to be different and such a discrepancy increases considerably as bones yield, suggesting a possible interfacial deformation between the two phases. In addition, hydration state of bone exhibits a significant role in sustaining the toughness of bone, but such effects diminish for elderly bones. Moreover, evidence has shown that age-related accumulation of non-enzymatic collagen crosslinks in bone may have significant effects on the toughness of bone. In these cases, elderly bones tend to fail prematurely with very limited permanent (or plastic) deformation compared with the younger bones. Based on these recent findings, the central hypothesis of this study is that the capacity of post-yield energy dissipation in bone is mainly determined by the interaction between the mineral and collagen phases, and any adverse changes in such a interaction would consequently lead to an increased fragility of bone. Four specific aims will be addressed: Aim 1: To determine the mechanism of the post-yield behavior of bone under different loading modes. Working hypothesis: The post-yield behavior of bone is initiated with an acute increase in microdamage accumulation with large variation in viscous response (Stage I) and followed by a saturated viscous response associated with large plastic deformation (Stage II);and such a behavior is independent of loading modes. Aim 2: To determine the correlation of mineral/collagen interaction with the post-yield deformation and energy dissipation of bone. Working hypothesis: Deformation at the mineral and collagen interface is a major mechanism for energy dissipation during the post-yield deformation of bone. Aim 3: To determine the effect of dehydration on the interfacial behavior between the mineral and collagen phases in bone and its correlation with age. Working hypothesis: The interfacial interaction between the mineral and collagen phase of bone is significantly affected by dehydration, and such an effect diminishes with increasing age. Aim 4: To determine the role of non-enzymatic collagen crosslinks (AGEs) in affecting the post-yield behavior (toughness) of bone and its correlation with age. Working hypothesis: Age-related accumulation of AGEs significantly affects the interfacial behavior between the mineral and collagen phases, thus leading to the significantly reduced capacity for bone to dissipate energy during the post-yield deformation. Through this study, we expect to elucidate the post-yield and failure behavior of bone at ultrastructural levels, and to determine the ultrastructural factors that govern the fragility of bone. Such information would facilitate future development of clinical treatments and strategies for predicting and preventing bone fractures. PUBLIC HEALTH RELEVANCE: The scientific and clinical relevance of this study is manifested in the following aspects: This study will help elucidate the underlying mechanism of the post-yield and failure behavior of bone at ultrastructural levels, thus allowing for accurate modeling and failure prediction of bone in musculoskeletal and implant systems. In addition, the novel techniques of this study will provide a unique means to help identify the cellular/molecular pathways that cause such ultrastructural changes in bone during pathological processes and to evaluate the efficacy of clinical treatments to bone disorders. Finally, by further modifications this approach can be extended to assess ultrastructural changes in biopsy bone tissues quantitatively, thus helping physicians to make more accurate risk assessments of bone fractures.